In experiments outlined herein we show that blood plasma causes coronary vasoconstriction in isolated rabbit hearts perfused with Tyrode's solution. Furthermore, cardiac regulation of coronary flow to changes in perfusion pressure, or perfusate oxygen tension occurs in the presence of plasma but not in its absence. A clue to the role of plasma in the regulation of coronary flow came from studies using inhibitors of prostaglandin synthesis such as indomethacin or 5,8,11,14-eicosatetraynoic acid. When infused into isolated rabbit hearts, these compounds abolished the effects of plasma. These results suggest that there is a moderate, basal level of prostaglandin synthesis in the normal blood perfused heart. The prostaglandins resulting from this synthesis cause coronary vasoconstriction. The degree of coronary vasoconstriction may be related to the rate of prostaglandin synthesis. This hypothesis is appealing since molecular (gaseous) oxygen is required in the synthesis of prostaglandins. If the oxygen concentration were rate limiting, then a decrease in the availability of oxygen would decrease prostaglandin synthesis and lead to an increase in flow. In preliminary experiments we found that lowering the perfusate oxygen tension resulted in a decrease in prostaglandin-like activity in the coronary effluent (accompanied by increase in coronary flow). Inhibiting prostaglandin synthesis with indomethacin produced identical changes in prostaglandin-like activity and coronary flow. These results support our hypothesis. We plan to further test this hypothesis by (1) identifying the specific prostaglandins in the coronary effluent, (2) studying their effect upon the heart, (3) establishing the changes in the synthesis and release of these prostaglandins during regulatory responses, and (4) determining the chemical nature of the active substance in plasma. Isolated heart preparations and hearts in vivo will be used in these studies.